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1. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

Author

Andrikopoulos, Petros, Aron-Wisnewsky, Judith, Chakaroun, Rima, Myridakis, Antonis, Forslund, Sofia K., Nielsen, Trine, Adriouch, Solia, Holmes, Bridget, Chilloux, Julien, Vieira-Silva, Sara, Falony, Gwen, Salem, Joe-Elie, Andreelli, Fabrizio, Belda, Eugeni, Kieswich, Julius, Chechi, Kanta, Puig-Castellvi, Francesc, Chevalier, Mickael, Le Chatelier, Emmanuelle, Olanipekun, Michael T., Hoyles, Lesley, Alves, Renato, Helft, Gerard, Isnard, Richard, Køber, Lars, Coelho, Luis Pedro, Rouault, Christine, Gauguier, Dominique, Gøtze, Jens Peter, Prifti, Edi, Froguel, Philippe, Zucker, Jean-Daniel, Bäckhed, Fredrik, Vestergaard, Henrik, Hansen, Torben, Oppert, Jean-Michel, Blüher, Matthias, Nielsen, Jens, Raes, Jeroen, Bork, Peer, Yaqoob, Muhammad M., Stumvoll, Michael, Pedersen, Oluf, Ehrlich, S. Dusko, Clément, Karine, and Dumas, Marc-Emmanuel

Published
2023
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5. Microbiome and metabolome features of the cardiometabolic disease spectrum

Author

Fromentin, Sebastien, Forslund, Sofia K., Chechi, Kanta, Aron-Wisnewsky, Judith, Chakaroun, Rima, Nielsen, Trine, Tremaroli, Valentina, Ji, Boyang, Prifti, Edi, Myridakis, Antonis, Chilloux, Julien, Andrikopoulos, Petros, Fan, Yong, Olanipekun, Michael T., Alves, Renato, Adiouch, Solia, Bar, Noam, Talmor-Barkan, Yeela, Belda, Eugeni, Caesar, Robert, Coelho, Luis Pedro, Falony, Gwen, Fellahi, Soraya, Galan, Pilar, Galleron, Nathalie, Helft, Gerard, Hoyles, Lesley, Isnard, Richard, Le Chatelier, Emmanuelle, Julienne, Hanna, Olsson, Lisa, Pedersen, Helle Krogh, Pons, Nicolas, Quinquis, Benoit, Rouault, Christine, Roume, Hugo, Salem, Joe-Elie, Schmidt, Thomas S. B., Vieira-Silva, Sara, Li, Peishun, Zimmermann-Kogadeeva, Maria, Lewinter, Christian, Søndertoft, Nadja B., Hansen, Tue H., Gauguier, Dominique, Gøtze, Jens Peter, Køber, Lars, Kornowski, Ran, Vestergaard, Henrik, Hansen, Torben, Zucker, Jean-Daniel, Hercberg, Serge, Letunic, Ivica, Bäckhed, Fredrik, Oppert, Jean-Michel, Nielsen, Jens, Raes, Jeroen, Bork, Peer, Stumvoll, Michael, Segal, Eran, Clément, Karine, Dumas, Marc-Emmanuel, Ehrlich, S. Dusko, and Pedersen, Oluf

Published
2022
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6. Stimulation of insulin secretion induced by low 4-cresol dose involves the RPS6KA3 signalling pathway.

Author

Brial, François, Puel, Géraldine, Gonzalez, Laurine, Russick, Jules, Auld, Daniel, Lathrop, Mark, Poirier, Roseline, Matsuda, Fumihiko, and Gauguier, Dominique

Subjects
WEIGHT loss, G protein coupled receptors, INSULIN regulation, INSULIN sensitivity, TYPE 2 diabetes, INSULIN
Abstract

4-cresol (4-methylphenol, p-cresol) is a xenobiotic substance negatively correlated with type 2 diabetes and associated with health improvement in preclinical models of diabetes. We aimed at refining our understanding of the physiological role of this metabolite and identifying potential signalling mechanisms. Functional studies revealed that 4-cresol does not deteriorate insulin sensitivity in human primary adipocytes and exhibits an additive effect to that of insulin on insulin sensitivity in mouse C2C12 myoblasts. Experiments in mouse isolated islets showed that 4-cresol potentiates glucose induced insulin secretion. We demonstrated the absence of off target effects of 4-cresol on a panel of 44 pharmacological compounds. Screening large panels of 241 G protein-coupled receptors (GPCRs) and 468 kinases identified binding of 4-cresol only to TNK1, EIF2AK4 (GCN2) and RPS6KA3 (RSK2), a kinase strongly expressed in human and rat pancreatic islets. Islet expression of RPS6KA3 is reduced in spontaneously diabetic rats chronically treated with 4-cresol and Rps6ka3 deficient mice exhibit reduction in both body weight and fasting glycemia, modest improvement in glycemic control and enhanced insulin release in vivo. Similar to low doses of 4-cresol, incubation of isolated rat islets with low concentrations of the RPS6KA3 inhibitor BIX 02565 stimulates both glucose induced insulin secretion and β-cell proliferation. These results provide further information on the role of low 4-cresol doses in the regulation of insulin secretion. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons

Author

Calderari, Sophie, Ria, Massimiliano, Gérard, Christelle, Nogueira, Tatiane C., Villate, Olatz, Collins, Stephan C., Neil, Helen, Gervasi, Nicolas, Hue, Christophe, Suarez-Zamorano, Nicolas, Prado, Cécilia, Cnop, Miriam, Bihoreau, Marie-Thérèse, Kaisaki, Pamela J., Cazier, Jean-Baptiste, Julier, Cécile, Lathrop, Mark, Werner, Michel, Eizirik, Decio L., and Gauguier, Dominique

Published
2018
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12. Genome-wide diversity in the levant reveals recent structuring by culture.

Author

Haber, Marc, Gauguier, Dominique, Youhanna, Sonia, Patterson, Nick, Moorjani, Priya, Botigué, Laura, Platt, Daniel, Matisoo-Smith, Elizabeth, Soria-Hernanz, David, Wells, R, Bertranpetit, Jaume, Tyler-Smith, Chris, Comas, David, and Zalloua, Pierre

Subjects
African Continental Ancestry Group, Archaeology, Chromosomes, Human, Y, Cultural Evolution, DNA, Mitochondrial, Ethnic Groups, European Continental Ancestry Group, Genetic Variation, Genetics, Population, Genome, Human, Haplotypes, Humans, Middle East, Phylogeny
Abstract

The Levant is a region in the Near East with an impressive record of continuous human existence and major cultural developments since the Paleolithic period. Genetic and archeological studies present solid evidence placing the Middle East and the Arabian Peninsula as the first stepping-stone outside Africa. There is, however, little understanding of demographic changes in the Middle East, particularly the Levant, after the first Out-of-Africa expansion and how the Levantine peoples relate genetically to each other and to their neighbors. In this study we analyze more than 500,000 genome-wide SNPs in 1,341 new samples from the Levant and compare them to samples from 48 populations worldwide. Our results show recent genetic stratifications in the Levant are driven by the religious affiliations of the populations within the region. Cultural changes within the last two millennia appear to have facilitated/maintained admixture between culturally similar populations from the Levant, Arabian Peninsula, and Africa. The same cultural changes seem to have resulted in genetic isolation of other groups by limiting admixture with culturally different neighboring populations. Consequently, Levant populations today fall into two main groups: one sharing more genetic characteristics with modern-day Europeans and Central Asians, and the other with closer genetic affinities to other Middle Easterners and Africans. Finally, we identify a putative Levantine ancestral component that diverged from other Middle Easterners ∼23,700-15,500 years ago during the last glacial period, and diverged from Europeans ∼15,900-9,100 years ago between the last glacial warming and the start of the Neolithic.

Published
2013

15. Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance

Author

Dumas, Marc-Emmanuel, Rothwell, Alice R., Hoyles, Lesley, Aranias, Thomas, Chilloux, Julien, Calderari, Sophie, Noll, Elisa M., Péan, Noémie, Boulangé, Claire L., Blancher, Christine, Barton, Richard H., Gu, Quan, Fearnside, Jane F., Deshayes, Chloé, Hue, Christophe, Scott, James, Nicholson, Jeremy K., and Gauguier, Dominique

Published
2017
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21. Plasma and urine metabolomic analyses in aortic valve stenosis reveal shared and biofluid-specific changes in metabolite levels

Author

Al Hageh, Cynthia, Rahy, Ryan, Khazen, Georges, Brial, Francois, Khnayzer, Rony S., Gauguier, Dominique, Zalloua, Pierre A., Al Hageh, Cynthia, Rahy, Ryan, Khazen, Georges, Brial, Francois, Khnayzer, Rony S., Gauguier, Dominique, and Zalloua, Pierre A.

Abstract

Aortic valve stenosis (AVS) is a prevalent condition among the elderly population that eventually requires aortic valve replacement. The lack of reliable biomarkers for AVS poses a challenge for its early diagnosis and the application of preventive measures. Untargeted gas chromatography mass spectrometry (GC-MS) metabolomics was applied in 46 AVS cases and 46 controls to identify plasma and urine metabolites underlying AVS risk. Multivariate data analyses were performed on pre-processed data (e.g. spectral peak alignment), in order to detect changes in metabolite levels in AVS patients and to evaluate their performance in group separation and sensitivity of AVS prediction, followed by regression analyses to test for their association with AVS. Through untargeted analysis of 190 urine and 130 plasma features that could be detected and quantified in the GC-MS spectra, we identified contrasting levels of 22 urine and 21 plasma features between AVS patients and control subjects. Following metabolite assignment, we observed significant changes in the concentration of known metabolites in urine (n = 14) and plasma (n = 15) that distinguish the metabolomic profiles of AVS patients from healthy controls. Associations with AVS were replicated in both plasma and urine for about half of these metabolites. Among these, 2-Oxovaleric acid, elaidic acid, myristic acid, palmitic acid, estrone, myo-inositol showed contrasting trends of regulation in the two biofluids. Only trans-Aconitic acid and 2,4-Di-tert-butylphenol showed consistent patterns of regulation in both plasma and urine. These results illustrate the power of metabolomics in identifying potential disease-associated biomarkers and provide a foundation for further studies towards early diagnostic applications in severe heart conditions that may prevent surgery in the elderly.

Published
2023

22. Elevated Lp(a) Levels Correlate with Severe and Multiple Coronary Artery Stenotic Lesions

Author

Al Hageh,Cynthia, Chacar,Stephanie, Ghassibe-Sabbagh,Michella, Platt,Daniel E, Henschel,Andreas, Hamdan,Hamdan, Gauguier,Dominique, El Murr,Yara, Alefishat,Eman, Chammas,Elie, O'Sullivan,Siobhán, Abchee,Antoine, Nader,Moni, Zalloua,Pierre A, Al Hageh,Cynthia, Chacar,Stephanie, Ghassibe-Sabbagh,Michella, Platt,Daniel E, Henschel,Andreas, Hamdan,Hamdan, Gauguier,Dominique, El Murr,Yara, Alefishat,Eman, Chammas,Elie, O'Sullivan,Siobhán, Abchee,Antoine, Nader,Moni, and Zalloua,Pierre A

Abstract

Cynthia Al Hageh,1,* Stephanie Chacar,2,* Michella Ghassibe-Sabbagh,3 Daniel E Platt,4 Andreas Henschel,5 Hamdan Hamdan,2 Dominique Gauguier,6,7 Yara El Murr,3 Eman Alefishat,8,9 Elie Chammas,10 Siobhán O’Sullivan,1 Antoine Abchee,11 Moni Nader,2,9 Pierre A Zalloua1,9,12 1Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; 2Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; 3Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon; 4Computational Biology Center, IBM TJ Watson Research Centre, Yorktown Hgts, NY, USA; 5Department of Electrical Engineering and Computer, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; 6Université Paris Cité, INSERM UMR 1124, Paris, 75006, France; 7McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada; 8Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; 9Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, 127788, United Arab Emirates; 10School of Medicine, Lebanese University, Beirut, Lebanon; 11Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates; 12Harvard T.H. Chan School of Public Health, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Pierre A Zalloua; Moni Nader, College of Medicine and Health Sciences, Khalifa University for Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates, Email pierre.zalloua@ku.ac.ae; moni.nader@ku.ac.aeBackgrounds and Aims: The role of Lipoprotein(a) (Lp(a)) in increasing the risk of cardiovascular diseases is reported in several populations. The aim o

Published
2023

23. Genetic Variants in PHACTR1 & LPL Mediate Restenosis Risk in Coronary Artery Patients

Author

Al Hageh,Cynthia, Chacar,Stephanie, Venkatachalam,Thenmozhi, Gauguier,Dominique, Abchee,Antoine, Chammas,Elie, Hamdan,Hamdan, O'Sullivan,Siobhan, Zalloua,Pierre, Nader,Moni, Al Hageh,Cynthia, Chacar,Stephanie, Venkatachalam,Thenmozhi, Gauguier,Dominique, Abchee,Antoine, Chammas,Elie, Hamdan,Hamdan, O'Sullivan,Siobhan, Zalloua,Pierre, and Nader,Moni

Abstract

Cynthia Al Hageh,1,* Stephanie Chacar,2,* Thenmozhi Venkatachalam,2 Dominique Gauguier,3,4 Antoine Abchee,5 Elie Chammas,6 Hamdan Hamdan,2 Siobhan O’Sullivan,1 Pierre Zalloua,1,7,8 Moni Nader2,7 1Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University for Science and Technology, Abu Dhabi, United Arab Emirates; 2Department of Physiology and Immunology College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, UAE; 3McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada; 4Université Paris Cité, INSERM, Paris, France; 5Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates; 6School of Medicine, Lebanese University, Beirut, Lebanon; 7Biotechnology Center, Khalifa University for Science and Technology, Abu Dhabi, United Arab Emirates; 8Harvard T.H. Chan School of Public Health, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Pierre Zalloua; Moni Nader, College of Medicine and Health Sciences, Khalifa University for Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates, Email pierre.zalloua@ku.ac.ae; moni.nader@ku.ac.aeBackground and Objective: Coronary artery disease (CAD) is a major cause of death worldwide. Revascularization via stent placement or coronary artery bypass grafting (CABG) are standard treatments for CAD. Despite a high success rate, these approaches are associated with long-term failure due to restenosis. Risk factors associated with restenosis were investigated using a case-control association study design.Methods: Five thousand two hundred and forty-two patients were enrolled in this study and were assigned as follows: Stenosis Group: 3570 patients with CAD > 50% without a prior stent or CABG (1394 genotyped), and Restenosis Group: 1672 patients with CAD > 50% and prior stent deployment or CABG (705 genotyped). Binomial regression models were appli

Published
2023

24. The impact of forced displacement: trauma, increased levels of inflammation and early presentation of diabetes in women Syrian refugees

Author

Venkatachalam, Thenmozhi, primary, O'Sullivan, Siobhán, additional, Platt, Daniel E, additional, Ammar, Walid, additional, Hamadeh, Randa, additional, Riachi, Naji, additional, Presley, Diane, additional, Khoury, Brigitte, additional, Gauguier, Dominique, additional, Nader, Moni, additional, Qi, Lu, additional, and Zalloua, Pierre, additional

Published
2023
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29. Elevated Lp(a) Levels Correlate with Severe and Multiple Coronary Artery Stenotic Lesions

Author

Al Hageh, Cynthia, primary, Chacar, Stephanie, additional, Ghassibe-Sabbagh, Michella, additional, Platt, Daniel E, additional, Henschel, Andreas, additional, Hamdan, Hamdan, additional, Gauguier, Dominique, additional, El Murr, Yara, additional, Alefishat, Eman, additional, Chammas, Elie, additional, O'Sullivan, Siobhán, additional, Abchee, Antoine, additional, Nader, Moni, additional, and Zalloua, Pierre A, additional

Published
2023
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30. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamineN-oxide with implications for heart and kidney disorders

Author

Andrikopoulos, Petros, Aron-Wisnewsky, Judith, Chakaroun, Rima, Myridakis, Antonis, Forslund, Sofia, Nielsen, Trine, Adriouch, Solia, Holmes, Bridget, Chilloux, Julien, Vieira-Silva, Sara, Falony, Gwen, Salem, Joe-Elie, Andreelli, Fabrizio, Belda, Eugeni, Kieswich, Julius, Chechi, Kanta, Puig-Castellvi, Francesc, Chevalier, Mickael, Le Chatelier, Emmanuelle, Olanipekun, Michael, Hoyles, Lesley, Alves, Renato, Helft, Gerard, Isnard, Richard, Køber, Lars, Pedro Coelho, Luis, Rouault, Christine, Gauguier, Dominique, Gøtze, Jens Peter, Prifti, Edi, Zucker, Jean-Daniel, Bäckhed, Fredrik, Vestergaard, Henrik, Hansen, Torben, Oppert, Jean-Michel, Blüher, Matthias, Nielsen, Jens, Raes, Jeroen, Bork, Peer, Yaqoob, Muhammad, Stumvoll, Michael, Pedersen, Oluf, Ehrlich, S. Dusko, Clément, Karine, Dumas, Marc-Emmanuel, Imperial College London, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universitätsklinikum Leipzig, European Molecular Biology Laboratory [Heidelberg] (EMBL), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Paris-Saclay Food and Bioproduct Engineering (SayFood), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Procédés biotechnologiques au service de l'environnement (UR PROSE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Charles Viollette (ICV) - ULR 7394 (ICV), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Institut Supérieur d'Agriculture-Université de Lille-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaGenoPolis (MGP (US 1367)), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

ObjectivesThe host-microbiota co-metabolite trimethylamineN-oxide (TMAO) is linked to increased thrombotic and cardiovascular risks. Here we, sought to i) characterize which host variables contribute to fasting serum TMAO levels in real-life settings ii) identify potential actionable therapeutic means related to circulating TMAO.DesignWe applied “explainable” machine learning, univariate-, multivariate- and mediation analyses of fasting plasma TMAO concentration and a multitude of bioclinical phenotypes in 1,741 adult Europeans of the MetaCardis study. We expanded and validated our epidemiological findings in mechanistic studies in human renal fibroblasts and a murine model of kidney fibrosis following TMAO exposure.ResultsNext to age, kidney function was the primary variable predicting circulating TMAO in MetaCardis, with microbiota composition and diet playing minor, albeit significant roles. Mediation analysis revealed a causal relationship between TMAO and kidney function decline that strengthened at more severe stages of cardiometabolic disease. We corroborated our findings in preclinical models where TMAO exposure augmented conversion of human renal fibroblasts into myofibroblasts and increased kidney scarringin vivo. Mechanistically, TMAO aggravated kidney fibrosis due to ERK1/2 hyperactivation synergistically with TGF-β1 signaling. Consistent with our findings, patients receiving next-generation glucose-lowering drugs with reno-protective properties, had significantly lower circulating TMAO when compared to propensity-score matched control individuals.ConclusionAfter age, kidney function is the major determinant of fasting circulating TMAO in adults. Our findings of lower TMAO levels in individuals medicated with reno-protective anti-diabetic drugs suggests a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk that merits urgent investigation in human trials.Data availability statementRaw shotgun sequencing data that support the findings of this study have been deposited in the European Nucleotide Archive with accession codes PRJEB37249, PRJEB38742, PRJEB41311 and PRJEB46098. Serum NMR and urine NMR metabolome data have been uploaded to Metabolights with accession number MTBLS3429; serum GC-MS and isotopically quantified serum metabolites (UPLC–MS/MS) are available from MassIVE with accession numbers MSV000088042 and MSV000088043, respectively.

Published
2022
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32. Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

Author

Atanur, Santosh S., Diaz, Ana Garcia, Maratou, Klio, Sarkis, Allison, Rotival, Maxime, Game, Laurence, Tschannen, Michael R., Kaisaki, Pamela J., Otto, Georg W., Ma, Man Chun John, Keane, Thomas M., Hummel, Oliver, Saar, Kathrin, Chen, Wei, Guryev, Victor, Gopalakrishnan, Kathirvel, Garrett, Michael R., Joe, Bina, Citterio, Lorena, Bianchi, Giuseppe, McBride, Martin, Dominiczak, Anna, Adams, David J., Serikawa, Tadao, Flicek, Paul, Cuppen, Edwin, Hubner, Norbert, Petretto, Enrico, Gauguier, Dominique, Kwitek, Anne, Jacob, Howard, and Aitman, Timothy J.

Published
2013
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33. Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk

Author

Ghassibe-Sabbagh, Michella, Platt, Daniel E., Youhanna, Sonia, Abchee, Antoine B., Stewart, Krista, Badro, Danielle A., Haber, Marc, Salloum, Angelique K., Douaihy, Bouchra, el Bayeh, Hamid, Othman, Raed, Shasha, Nabil, Kibbani, Samer, Chammas, Elie, Milane, Aline, Nemr, Rita, Kamatani, Yoichiro, Hager, Jörg, Cazier, Jean-Baptiste, Gauguier, Dominique, and Zalloua, Pierre A.

Published
2012
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37. Circulating lipid levels and risk of coronary artery disease in a large group of patients undergoing coronary angiography

Author

Platt, Daniel E., Ghassibe-Sabbagh, Michella, Youhanna, Sonia, Hager, Jörg, Cazier, Jean-Baptiste, Kamatani, Yoichiro, Salloum, Angelique K., Haber, Marc, Romanos, Jihane, Doueihy, Bouchra, Mouzaya, Francis, Kibbani, Samer, Sbeite, Hana, Deeb, Mary E., Chammas, Elie, el Bayeh, Hamid, Khazen, Georges, Gauguier, Dominique, Zalloua, Pierre A., Abchee, Antoine B., and FGENTCARD Consortium

Published
2015
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39. Genetic Variants in PHACTR1 & LPL Mediate Restenosis Risk in Coronary Artery Patients.

Author

Hageh, Cynthia Al, Chacar, Stephanie, Venkatachalam, Thenmozhi, Gauguier, Dominique, Abchee, Antoine, Chammas, Elie, Hamdan, Hamdan, O'Sullivan, Siobhan, Zalloua, Pierre, and Nader, Moni

Subjects
GENETIC variation, CORONARY artery disease, REVASCULARIZATION (Surgery), REGRESSION analysis, PEOPLE with diabetes
Abstract

Background and Objective: Coronary artery disease (CAD) is a major cause of death worldwide. Revascularization via stent placement or coronary artery bypass grafting (CABG) are standard treatments for CAD. Despite a high success rate, these approaches are associated with long-term failure due to restenosis. Risk factors associated with restenosis were investigated using a case-control association study design. Methods: Five thousand two hundred and forty-two patients were enrolled in this study and were assigned as follows: Stenosis Group: 3570 patients with CAD > 50% without a prior stent or CABG (1394 genotyped), and Restenosis Group: 1672 patients with CAD > 50% and prior stent deployment or CABG (705 genotyped). Binomial regression models were applied to investigate the association of restenosis with diabetes, hypertension, and dyslipidemia. The genetic association with restenosis was conducted using PLINK 1.9. Results: Dyslipidemia is a major risk factor (Odds Ratio (OR) = 2.14, P-value < 0.0001) for restenosis particularly among men (OR = 2.32, P < 0.0001), while type 2 diabetes (T2D) was associated with an increased risk of restenosis in women (OR = 1.36, P = 0.01). The rs9349379 (PHACTR1) and rs264 (LPL) were associated with an increased risk of restenosis in our patients. PHACTR1 variant was associated with increased risk of restenosis mainly in women and in diabetic patients, while the LPL variant was associated with increased risk of restenosis in men. Conclusion: The rs9349379 in PHACTR1 gene is significantly associated with restenosis, this association is more pronounced in women and in diabetic patients. The rs264 in LPL gene was associated with increased risk of restenosis in male patients. [ABSTRACT FROM AUTHOR]

Published
2023
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40. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J., Dahia, Chitra L., Park-Min, Kyung Hyun, Tobias, Jonathan H., Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S., Nielson, Carrie M., Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E., Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A., Gregson, Celia L., Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J., Marshall, Mhairi, Gardiner, Brooke B., Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y., Thorleifsson, Gudmar, Enneman, Anke W., van Schoor, Natasja M., de Groot, Lisette C. P. G. M., van der Velde, Nathalie, Melin, Beatrice, Kemp, John P., Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G., Williams, Stephen R., Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z., Haessler, Jeff, Chasman, Daniel I., Giulianini, Franco, Rose, Lynda M., Ridker, Paul M., Eisman, John A., Nguyen, Tuan V., Center, Jacqueline R., Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L., Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P., Koromani, Fjorda, Prince, Richard L., Lewis, Joshua R., Langdahl, Bente L., Hermann, Pernille A., Jensen, Jens-Erik B., Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M., Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E., Garg, Gaurav, Olmos, Jose M., Zarrabeitia, Maria T., Riancho, Jose A., Ralston, Stuart H., Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S., Karasik, David, Davey-Smith, George, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, Carola M., van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, Scott G., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, Adrienne L., Ohlsson, Claes, Greenwood, Celia M. T., Jackson, Rebecca D., Rowe, David W., Loomis, Cynthia A., Evans, David M., Ackert-Bicknell, Cheryl L., Joyner, Alexandra L., Duncan, Emma L., Kiel, Douglas P., Rivadeneira, Fernando, and Richards, Brent J.

Published
2015
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42. Elevated Lp(a) Levels Correlate with Severe and Multiple Coronary Artery Stenotic Lesions.

Author

Hageh, Cynthia Al, Chacar, Stephanie, Ghassibe-Sabbagh, Michella, Platt, Daniel E, Henschel, Andreas, Hamdan, Hamdan, Gauguier, Dominique, El Murr, Yara, Alefishat, Eman, Chammas, Elie, O'Sullivan, Siobhán, Abchee, Antoine, Nader, Moni, and Zalloua, Pierre A

Subjects
CORONARY artery stenosis, LIPOPROTEINS, CARDIOVASCULAR diseases risk factors, CORONARY angiography, BIOMARKERS
Abstract

Backgrounds and Aims: The role of Lipoprotein(a) (Lp(a)) in increasing the risk of cardiovascular diseases is reported in several populations. The aim of this study is to investigate the correlation of high Lp(a) levels with the degree of coronary artery stenosis. Methods: Two hundred and sixty-eight patients were enrolled for this study. Patients who underwent coronary artery angiography and who had Lp(a) measurements available were included in this study. Binomial logistic regressions were applied to investigate the association between Lp(a) and stenosis in the four major coronary arteries. The effect of LDL and HDL Cholesterol on modulating the association of Lp(a) with coronary artery disease (CAD) was also evaluated. Multinomial regression analysis was applied to assess the association of Lp(a) with the different degrees of stenosis in the four major coronary arteries. Results: Our analyses showed that Lp(a) is a risk factor for CAD and this risk is significantly apparent in patients with HDL-cholesterol ≥ 35 mg/dL and in non-obese patients. A large proportion of the study patients with elevated Lp(a) levels had CAD even when exhibiting high HDL serum levels. Increased HDL with low Lp(a) serum levels were the least correlated with stenosis. A significantly higher levels of Lp(a) were found in patients with > 50% stenosis in at least two major coronary vessels arguing for pronounced and multiple stenotic lesions. Finally, the derived variant (rs1084651) of the LPA gene was significantly associated with CAD. Conclusion: Our study highlights the importance of Lp(a) levels as an independent biological marker of severe and multiple coronary artery stenosis. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Human and preclinical studies of the host–gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health

Author

Brial, François, primary, Chilloux, Julien, additional, Nielsen, Trine, additional, Vieira-Silva, Sara, additional, Falony, Gwen, additional, Andrikopoulos, Petros, additional, Olanipekun, Michael, additional, Hoyles, Lesley, additional, Djouadi, Fatima, additional, Neves, Ana L, additional, Rodriguez-Martinez, Andrea, additional, Mouawad, Ghiwa Ishac, additional, Pons, Nicolas, additional, Forslund, Sofia, additional, Le-chatelier, Emmanuelle, additional, Le Lay, Aurélie, additional, Nicholson, Jeremy, additional, Hansen, Torben, additional, Hyötyläinen, Tuulia, additional, Clément, Karine, additional, Oresic, Matej, additional, Bork, Peer, additional, Ehrlich, Stanislav Dusko, additional, Raes, Jeroen, additional, Pedersen, Oluf Borbye, additional, Gauguier, Dominique, additional, and Dumas, Marc-Emmanuel, additional

Published
2021
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46. Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health

Author

Brial, Francois, Chilloux, Julien, Nielsen, Trine, Vieira-Silva, Sara, Falony, Gwen, Andrikopoulos, Petros, Olanipekun, Michael, Hoyles, Lesley, Djouadi, Fatima, Neves, Ana L., Rodriguez-Martinez, Andrea, Mouawad, Ghiwa Ishac, Pons, Nicolas, Forslund, Sofia, Le-chatelier, Emmanuelle, Le Lay, Aurelie, Nicholson, Jeremy, Hansen, Torben, Hyotylainen, Tuulia, Clement, Karine, Oresic, Matej, Bork, Peer, Ehrlich, Stanislav Dusko, Raes, Jeroen, Pedersen, Oluf Borbye, Gauguier, Dominique, Dumas, Marc-Emmanuel, Brial, Francois, Chilloux, Julien, Nielsen, Trine, Vieira-Silva, Sara, Falony, Gwen, Andrikopoulos, Petros, Olanipekun, Michael, Hoyles, Lesley, Djouadi, Fatima, Neves, Ana L., Rodriguez-Martinez, Andrea, Mouawad, Ghiwa Ishac, Pons, Nicolas, Forslund, Sofia, Le-chatelier, Emmanuelle, Le Lay, Aurelie, Nicholson, Jeremy, Hansen, Torben, Hyotylainen, Tuulia, Clement, Karine, Oresic, Matej, Bork, Peer, Ehrlich, Stanislav Dusko, Raes, Jeroen, Pedersen, Oluf Borbye, Gauguier, Dominique, and Dumas, Marc-Emmanuel

Abstract

Objective Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health. Design In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied H-1-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes. Results In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion. Conclusion Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.

Published
2021

48. A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice

Author

Solberg, Leah C., Valdar, William, Gauguier, Dominique, Nunez, Graciela, Taylor, Amy, Burnett, Stephanie, Arboledas-Hita, Carmen, Hernandez-Pliego, Polinka, Davidson, Stuart, Burns, Peter, Bhattacharya, Shoumo, Hough, Tertius, Higgs, Douglas, Klenerman, Paul, Cookson, William O., Zhang, Youming, Deacon, Robert M., Rawlins, J. Nicholas P., Mott, Richard, and Flint, Jonathan

Published
2006
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49. Genetic and environmental effects on complex traits in mice

Author

Valdar, William, Solberg, Leah C., Gauguier, Dominique, Cookson, William O., Rawlins, J. Nicholas P., Mott, Richard, and Flint, Jonathan

Subjects
Behavior genetics -- Research, Genetic variation -- Research, Biological sciences
Abstract

The interaction between genotype and environment is recognized as an important source of experimental variation when complex traits are measured in the mouse, but the magnitude of that interaction has not often been measured. From a study of 2448 genetically heterogeneous mice, we report the heritability of 88 complex traits that include models of human disease (asthma, type 2 diabetes mellitus, obesity, and anxiety) as well as immunological, biochemical, and hematological phenotypes. We show that environmental and physiological covariates are involved in an unexpectedly large number of significant interactions with genetic background. The 15 covariates we examined have a significant effect on behavioral and physiological tests, although they rarely explain >10% of the variation. We found that interaction effects are more frequent and larger than the main effects: half of the interactions explained >20% of the variance and in nine cases exceeded 50%. Our results indicate that assays of gene function using mouse models should take into account interactions between gene and environment.

Published
2006

50. Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic [sup.1]H NMR data sets

Author

Cloarec, Olivier, Dumas, Marc-Emmanuel, Craig, Andrew, Barton, Richard H., Trygg, Johan, Hudson, Jane, Blancher, Christine, Gauguier, Dominique, Lindon, John C., Holmes, Elaine, and Nicholson, Jeremy

Subjects
Magnetic resonance imaging -- Research, Biological markers -- Research, Spectrum analysis -- Research, Chemistry, Analytic -- Research, Chemistry
Abstract

We describe here the implementation of the statistical total correlation spectroscopy (STOCSY) analysis method for aiding the identification of potential biomarker molecules in metabonomic studies based on NMR spectroscopic data. STOCSY takes advantage of the multicollinearity of the intensity variables in a set of spectra (in this case [sup.1]H NMR spectra) to generate a pseudo-two-dimensional NMR spectrum that displays the correlation among the intensities of the various peaks across the whole sample. This method is not limited to the usual connectivities that are deducible from more standard two-dimensional NMR spectroscopic methods, such as TOCSY. Moreover, two or more molecules involved in the same pathway can also present high intermolecular correlations because of biological covariance or can even be anticorrelated. This combination of STOCSY with supervised pattern recognition and particularly orthogonal projection on latent structure--discriminant analysis (O-PLS-DA) offers a new powerful framework for analysis of metabonomic data. In a first step O-PLS-DA extracts the part of NMR spectra related to discrimination. This information is then cross-combined with the STOCSY results to help identify the molecules responsible for the metabolic variation. To illustrate the applicability of the method, it has been applied to 1H NMR spectra of urine from a metabonomic study of a model of insulin resistance based on the administration of a carbohydrate diet to three different mice strains (C57BL/6Oxjr, BALB/cOxjr, and 129S6/SvEvOxjr) in which a series of metabolites of biological importance can be conclusively assigned and identified by use of the STOCSY approach.

Published
2005

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